Pyrazolo[3,4-d]pyrimidines as potent antiproliferative and proapoptotic agents toward A431 and 8701-BC cells in culture via inhibition of c-Src phosphorylation

被引:89
作者
Carraro, F
Naldini, A
Pucci, A
Locatelli, GA
Maga, G
Schenone, S
Bruno, O
Ranise, A
Bondavalli, F
Brullo, C
Fossa, P
Menozzi, G
Mosti, L
Modugno, M
Tintori, C
Manetti, F
Botta, M
机构
[1] Univ Genoa, Dipartimento Sci Farmaceut, I-16132 Genoa, Italy
[2] Univ Siena, Dipartimento Fisiol, Sez Neuroimmunofisiol, I-53100 Siena, Italy
[3] CNR, IGM, I-27100 Pavia, Italy
[4] Univ Siena, Dipartimento Farmaco Chim Tecnol, I-53100 Siena, Italy
关键词
D O I
10.1021/jm050603r
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
We report here the synthesis of new pyrazolo[3,4-d]pyrimidine derivatives along with their biological properties as inhibitors of isolated Src and cell line proliferation (A431 and 8701-BC cells). Such compounds block the growth of cancer cells by interfering with the phosphorylation of Src, and they act as proapoptotic agents through the inhibition of the anti apoptotic gene BCL2. Several of them were found to be more active than the reference compound (1-(tert-butyl)-3-(4-chlorophenyl)-4-aminopyrazolo[3,4-d]pyrimidine, PP2) in inhibiting cell proliferation and in inducing apoptosis, and as active as PP2 in the inhibition of the phosphorylation of isolated Src. Moreover, molecular modeling simulations have been performed to hypothesize the way, at the molecular level, by which the inhibitors were able to act as antiproliferative agents.
引用
收藏
页码:1549 / 1561
页数:13
相关论文
共 53 条
  • [1] Src family tyrosine kinases and growth factor signaling
    Abram, CL
    Courtneidge, SA
    [J]. EXPERIMENTAL CELL RESEARCH, 2000, 254 (01) : 1 - 13
  • [2] N7-Substituted-5-aryl-pyrrolo[2,3-d]pyrimidines Represent a Versatile Class of Potent Inhibitors of the Tyrosine Kinase c-Src
    Altmann, Eva
    Widler, Leo
    Missbach, Martin
    [J]. MINI-REVIEWS IN MEDICINAL CHEMISTRY, 2002, 2 (03) : 201 - 208
  • [3] Selected glimpses into the activation and function of Src kinase
    Bjorge, JD
    Jakymiw, A
    Fujita, DJ
    [J]. ONCOGENE, 2000, 19 (49) : 5620 - 5635
  • [4] Synthesis, molecular modeling studies, and pharmacological activity of selective A1 receptor antagonists
    Bondavalli, F
    Botta, M
    Bruno, O
    Ciacci, A
    Corelli, F
    Fossa, P
    Lucacchini, A
    Manetti, F
    Martini, C
    Menozzi, G
    Mosti, L
    Ranise, A
    Schenone, S
    Tafi, A
    Trincavelli, ML
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2002, 45 (22) : 4875 - 4887
  • [5] BOTTA M, UNPUB
  • [6] Regulation, substrates and functions of src
    Brown, MT
    Cooper, JA
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, 1996, 1287 (2-3): : 121 - 149
  • [7] BUDDE RJA, 1994, CANCER BIOCHEM BIOPH, V14, P171
  • [8] Further studies on ethenyl and ethynyl-4-phenylamino-3-quinolinecarbonitriles: identification of a subnanomolar Src kinase inhibitor
    Carolina, A
    Sosa, B
    Boschelli, DH
    Wu, BQ
    Wang, Y
    Golas, JM
    [J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (06) : 1743 - 1747
  • [9] Pyrazolo[3,4-d]pyrimidines endowed with antiproliferative activity on ductal infiltrating carcinoma cells
    Carraro, F
    Pucci, A
    Naldini, A
    Schenone, S
    Bruno, O
    Ranise, A
    Bondavalli, F
    Brullo, C
    Fossa, P
    Menozzi, G
    Mosti, L
    Manetti, F
    Botta, M
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (07) : 1595 - 1598
  • [10] Chen Y, 1999, CANCER EPIDEM BIOMAR, V8, P855